Y. Ishihara
Prof. Masakatsu Shibasaki
Masakatsu Shibasaki – 柴崎�正勝
Prof. Shibasaki's overall philosophy in chemistry:
「タキソール様の分子を、地球環境に負の効果をもたらす
ことなくトンスケールで合成できれば、有機合成は人類に
とって 100% の成熟度に達したと言えるのではないか」
(Unofficial translation: "If one could synthesize a
molecule the size of Taxol® in ton-scale, without
severely affecting our environment, one could then
arrive at the conclusion that organic synthesis has
matured to 100%.")
– Apr 2006 edition of 有機合成化学協会誌 (yuukigousei-kagaku-kyoukaishi)
Jan 25 1947 Born in Saitama, Japan
19XX–1974 Ph. D. in pharmaceutical sciences, The University of Tokyo
(Prof. Shun-ichi Yamada)
1974–1977 Postdoctoral fellow, Harvard University (Prof. Elias J. Corey)
1977–1983 Associate professor, Teikyo University (Prof. Shiro Ikegami)
1983–1986 Research group leader, Sagami Chemical Research Center
1986–1991 Professor, Hokkaido University
1991–2010 Professor, The University of Tokyo
2010–
Professor Emeritus, Hokkaido University and The University of Tokyo
2010–
Director of Chemistry and Representative Director, Institute of
Microbial Chemistry (commonly called "Bikaken" in Japan), Tokyo
Baran Lab GM 2011-05-28
533 Total number of papers as of May 2011
111
110
43
33
29
25
25
14
Tetrahedron Letters (TL)
Journal of the American Chemical Society (JACS)
The Journal of Organic Chemistry (JOC)
Angewandte Chemie, International Edition in English (ACIEE)
Tetrahedron (T)
Organic Letters (OL)
Chemical & Pharmaceutical Bulletin (CPB)
Chemistry Letters (CL)
If his life's works were to be summarized into one single sentence:
"Development of chiral catalysts for asymmetric reactions and application to the
synthesis of biologically active molecules."
His "chemical upbringing": Doctoral years in Tokyo
R2
R1
R2
R1
NH2
R3
R2
∆
R1
NC
R3
Me
N
H
R3
Thermal rearrangement of
isocyanides to cyanides and its
stereochemical implications:
CPB 1973, 21, 552 and 1868.
Me
R
Me
conc. H+
CHNR2
CHO
Me
CN
Me
Me
CHO
Me
Me
Me
Maximum of 33% ee: CPB 1975, 23, 272 and 279.
Shibasaki group picture
taken in Jan 2011:
His "chemical adolescence": Postdoc years at Harvard, teaming up with KC Nicolaou
O
6 postdocs
8 students
...+ others
"Professor Emeritus"
in Japan does not
really mean the same
as in the US!
O
MsCl, Et3N; KO2 (4 eq),
18-crown-6 (4.5 eq),
1:1:1 DMSO/DMF/DME
O
AcO
OH
C5H11 then PPh3; then LiOH;
then K2CO3, MeOH
(~75 %)
C5H11
HO
OH
TL 1975, 16, 3183.
CO2H
Z
Z
Current group website: http://bikaken.or.jp/research/group/shibasaki/shibasaki-lab/
A wikipedia page also exists: http://en.wikipedia.org/wiki/Masakatsu_Shibasaki
O
C5H11
OH
Z–Z is O–O → prostaglandin endoperoxide PGH2
Z–Z is HC=CH or N=N → bioactive mimic
TL 1976, 17, 737; JACS 1976, 98, 6417.
1
Masakatsu Shibasaki – 柴崎�正勝
Y. Ishihara
The early stages in his "chemical adulthood": Full Professor at Hokkaido
His "chemical apprenticeship": Associate professor at Teikyo University
HO2C
At first, he was still intrigued by tin compounds...
RC≡CH
RCH2CHO
Me
1) Bu3SnLi 2) CBr4/PPh3
3) DBU
4) Pb(OAc)4
65–70 % over 4 steps
TL 1982, 23, 4607.
Z
Br
C5H11
O
HO
CO2Et
1) Bu3SnLi 2) CBr4/PPh3
3) MCPBA 4) PCC
43–73 % over 4 steps
CL 1983, 12, 1303.
R1
CO2Me
Me
H
OAc
OH
H
NH3+
H
Me
N
O
R2 Me
Me
CO2–
H
N
O
R2
R1
NBn
SPh
BBN-O
NHAc
H
Me
Bu3SnSiMe3
Pd(PPh3)4
OH
S
O
CO2H
Formal synthesis of (–)-carpetimycin A:
TL 1985, 26, 2217.
R1
O
H
H
R
R
92% Bu3Sn
HI, Bu4NI
R
SiMe3
98%
SiMe3
Then he delved into Cr(CO)3 chemistry...
OTBS
OTBS
O-BBN
Formal synthesis of (+)-thienamycin:
TL 1985, 26, 1523
OH
(R1=H,
capnellenol
capnellenediol
R2=OH) and capnellenetriol (R1=R2=OH):
JACS 1986, 108, 2090; TL 1986, 27, 5245.
S
SnBu3
Comparison of the syntheses of Z- and E-vinylsilanes: CL 1991, 20, 1615.
H
(R1=R2=H),
Sn anion is more
nucleophilic toward
the alkene of an
enone rather than
the carbonyl: JOC
1993, 58, 2972.
O
Bu3SnSiMe3 (3 eq)
CsF (3 eq)
2) DIBAL
3) H3O+
OAc
Total synthesis of clavulone II:
TL 1985, 26, 3841.
OMe
I
R
OH
Me
Tandem
transmetalation–
cyclization: JOC
1991, 56, 3486.
Li2CO3 (1 eq),
PhMe, 110 ºC,
1.5 h (70%)
1) BuLi,
SiMe3 Me3SiCl
R
OH
CO2Et
DMF, 60 ºC, 1 h
(60%)
His "chemical independence": Group leader at Sagami Chemical Research Center
O
A mild stannyl
anion generation:
TL 1991, 32, 6139.
Bu3SnSiMe3 (1.1 eq)
PdCl2(PPh3)2 (3 mol%)
Bu4NBr (3 eq)
TfO
Br
O
O
OH
Br
R
Me
Bu3SnSiMe3
BnEt3NCl, DMF
74%
O
H
R
O
O
OH
More work on prostaglandins:
Z is O → prostacyclin PGI2
Z is CH2 or S → bioactive mimic
TL 1977, 18, 4037; TL 1978, 19, 559;
CL 1979, 8, 1299; TL 1980, 21, 169.
Baran Lab GM 2011-05-28
CHO
naphthalene–
Cr(CO)3 (20 mol%),
acetone, rt, 4 h, 98%
CO2Me
OTBS
CO2Me
This was followed by Diels–Alder to make a hydrindan: JACS 1990, 112, 4906.
Addition onto imine,
diastereoselectivities
ranged from 7:3 to 9:1:
TL 1985, 26, 1523; TL
1986, 27, 2153.
2
NHBn
SPh
MeO2C
NCO2Me
naphthalene–
MeO2C
Cr(CO)3 (20 mol%),
acetone, rt, 4 h, 89%
NCO2Me
Me
This was followed by Diels–Alder to make octahydroquinoline: JOC 1991, 56, 4569.
2
Masakatsu Shibasaki – 柴崎�正勝
Y. Ishihara
Prof. Shibasaki continued to work on β-lactams...
R
3.0 F/mol
(Bu4NBF4 as
electrolyte)
OAc
NH 1:9 AcOH/MeCN
O
O
O
R=H: 49%
R=CO2H: 76%
A finding that changed his career orientation: "Direct" aldol (JOC 1990, 55, 5308).
R1
NH
R2 CuOTf (1.2 eq) R1
CaCO3 (2 eq)
NHR3 PhMe, reflux
SR
(67–92 % yields) O
TL 1988, 29, 1409.
TiCl3 or TiCl4
THF, rt
O
X=CH2; 16 h, 48%
X=O; 24 h, 82%
NH
[THF•Mg2Cl2•TiN]
Me
JACS 1989, 111, 3725.
CO2 (1 atm)
THF, rt
[3THF•Mg2Cl2O•TiNCO]
He also continued to work on capnellenes...
...in the process, he discovered the first enantioselective Heck reaction: JOC
1989, 54, 4738. For Overman's version (90%, 45% ee), see: JOC 1989, 54, 5846.
CO2Me
I
NMP, 60 ºC
(74%, 46% ee)
Me
O
1) Protection
2) NaBH4
3) TsCl, DMAP
O
4) DBU
5) Deprotection
(56% overall)
Me O
Me
EtO2C
H
O
H
The choice of silver salt affects
enantioselectivity, reaching
70% ee for this same reaction:
CL 1990, 19, 1953. With vinyl
triflates, 91% ee was achieved:
TL 1992, 33, 2589.
Me
O
OTf
Zr(OtBu)4 (2 eq),
THF, –30 ºC to rt
OH
AcONa, Ac2O,
AcOH, 90 ºC
Me
Me
Me
Me
This cycloheptenone is "a useful intermediate for many natural product syntheses".
This sequence compares favorably to Smith's 4-step, 31% route (see Smith et al.,
JOC 1982, 47, 3960). Of note: "Owing to the bulkiness of both the tri-tert-butoxyzirconium cation and the counter tert-butoxy anion, the sterically favorable kinetic
enolate should be generated. Also the aldol reaction appears to proceed via an
acyclic transition state, thus avoiding the retro-aldol reaction".
A better alternative: "Rare earth" alkoxides (JACS 1992, 114, 4418).
O
O
OH
O
O
OTMS
A
Ph
R
C
Ph
R
Cl
O
R
TMSCN
Me O
B
OH Me O
O
Me Me O
CN
OH
NO2
R
Me
O
R
Cl
Me
O
HO
O
R'
D
NO2
R
R'
Bu4NOAc, DMSO, rt, 2.5 h
(89%, 80% ee)
Asymmetric reaction for reaction D using La3(OtBu)9 and BINOL: up to 91% and
90% ee was achieved. "Many applications [...] are under investigation."
Me
JOC 1991, 56, 4093.
Me
(Li, B, Zn, Zr, Sn
gave low yields)
Me
Pd(OAc)2 (1.7 mol%)
(S)-BINAP (2.1 mol%)
(62%)
Me
H
(79%)
A: Zr(OtBu)4 gave 86% yield at 140 mol% but 8% yield at 10 mol%. Ti(OtBu)4 gave
no product. La3(OtBu)9 gave 74% yield at 3.3 mol%, and Y3(OtBu)8Cl gave 50%
yield at 3.3 mol%.
B: Zr(OtBu)4 gave the axial alcohol product in 30% yield at 10 mol%. Al(OtBu)3 gave
no product. La3(OtBu)9 gave 40%+30% yields respectively of the product isomers
at 3.3 mol%, Y3(OtBu)8Cl gave 100% yield of the axial alcohol product at 3.3
mol%, and Y5(OiPr)13O gave 94% yield of the axial alcohol product at 2 mol%.
C, D: Great yields with La3(OtBu)9.
LDA, PhNTf2
H
Me
O
(78%)
O
Pd(OAc)2 (3 mol%)
(R)-BINAP (9 mol%)
Ag2CO3 (2 eq)
OBn
O
X
(A. Yamamoto et al., "storable powder" (P. Sobota et al., J. Organomet.
JCSCC 1969, 841.)
Chem. 1976, 118, 253.)
CO2Me
OH
(64% + 36% SM)
O
Me
NMP, 100 ºC
Mg
N2 (1 atm)
O
NR3
... then onto γ-lactams:
Br
Zr(OtBu)4 (1.5 eq), THF,
–40 ºC, then 6-BnO-2hexenal, –40 ºC, 15 min
O
R2
JOC 1989, 54, 3511.
Ti-NCO complex (3 eq)
XH
Pd(PPh3)4 (10 mol%)
K2CO3 (2 eq)
O
CO (1 atm)
Baran Lab GM 2011-05-28
OAc
3
Y. Ishihara
Masakatsu Shibasaki – 柴崎�正勝
The full blossoming of his "chemical adulthood": Full Professor at Tokyo
Following up on his findings in "rare earth" alkoxides, he starts to use/modify
known catalysts and make new ones for many types of asymmetric reactions.
What will be covered in this section:
1) BINOL-based heterometallic catalysts
2) BINOL-based catalysts activated by phosphine oxide or arsine oxide
3) BINOL-based Lewis acid/Lewis base bifunctional catalysts
4) BINOL-based bimetallic catalysts
5) Linked BINOL-based catalysts
6) Salen-derived, "Schiff base bimetallic" catalysts
7) Tartrate-derived catalysts
8) "CAPO" (catechol-phoshine oxide) ligands and "homopolymetallic" catalysts
9) Chiral Cu(I) catalysts
10) Amide-based catalysts
Major topics that will not be covered includes:
i) Asymmetric Heck reactions that characterized the early stages of his career
(e.g., see p.3 of this handout, left side). See reviews in T 1997, 53, 7371–
7395; Adv. Synth. Cat. 2004, 346, 1533–1552.
ii) Asymmetric catalysis with proline-derived ligands or bis(oxazoline) ligands.
iii) Non-asymmetric transformations, such as epoxidations of olefins using
TMSOOTMS (e.g., JACS 2000, 122, 1245; JACS 2001, 123, 1256), addition of
MeCN to RCHO with Ru catalysis (JACS 2004, 126, 13632), hydroamination
of 1,3-dienes using Bi catalysis (e.g., JACS 2006, 128, 1611), etc.
Nonradioactive Group 3 elements: Sc, Y
Nonradioactive Group 13 elements: B, Al, Ga, In, Tl
Lanthanide series, or "rare earth" elements: La (lanthanum), Ce (cerium), Pr
(praseodymium), Nd (neodymium), Pm (promethium), Sm (samarium), Eu
(europium), Gd (gadolinium), Tb (terbium), Dy (dysprosium), Ho (holmium), Er
(erbium), Tm (thulium), Yb (ytterbium) and Lu (lutetium).
Baran Lab GM 2011-05-28
1) BINOL-based heterometallic catalysts
For reviews by Shibasaki on this topic, see: Pure Appl. Chem. 1996, 68, 523–530;
ACIEE 1997, 36, 1236–1256; Pure Appl. Chem. 1998, 70, 1027–1034; Chem. Rev.
2002, 102, 2187–2210; Acc. Chem. Res. 2009, 42, 1117–1127.
Back in 1992 (see p.3 of handout, bottom right), Shibasaki reported in a footnote that
LiCl is essential to obtaining good enantioselectivity when using a La-BINOL ligand
for Henry reactions, but he did not know why: "It appears that LiCl plays a key role in
the formation of some oligomeric structure and also accelerates the reaction" (JACS
1992, 114, 4418).
Shibasaki notes later that Na ions can also be used (TL 1993, 34, 851), and also
does a screen of "rare earth" metal chlorides, La, Pr, Nd, Sm, Eu, Gd, Tb and Yb, as
well as group 3 metal chloride Y (TL 1993, 34, 2657).
Figures taken from Acc. Chem.
Res. 2009, 42, 1117 (left) and
JACS 1993, 115, 10372 (right).
Nomenclature system for these ligands, as used by the Shibasaki lab:
(R or S)-LnMB or (R or S)-REMB:
Ln = metal from the lanthanide series (conversely, RE = "rare earth" metal);
sometimes this is replaced with a group 3 or 13 metal
M = group 1 metal
B = binaphthoxide
Common Ln types: A (= Al), Ga, Y, L (= La), Pr, Nd, Sm, Eu, Gd, Tb, Dy, Yb
Common M types: L (= lithium), S (= sodium), P (= potassium)
e.g. (R)-ALB = (R)-AlLi3tris(binaphthoxide)
(S)-YbSB = (S)-YbNa3tris(binaphthoxide)
(S)-LPB = (S)-LaK3tris(binaphthoxide)
A debate arises (Salvadori et al., JACS 2003, 125, 5549) as to whether the
solution-phase structure of this catalyst differs from the crystal structure, and that
this C3-symmetric catalyst is actually a "pre-catalyst". A paper by Shibasaki
investigates whether three BINOL units in this complex is truly necessary, and he
studies kinetic behavior of these catalysts in solution, and concludes that the
trimeric form is the active form for catalysis (ACIEE 2004, 43, 4493).
4
Y. Ishihara
Masakatsu Shibasaki – 柴崎�正勝
Baran Lab GM 2011-05-28
Scope of the reaction: Any consonant
disconnection
Central metals used: Practically any group 3,
13 or "rare earth" metal
Also: asymmetric cyclopropanation
of enones (JACS 2007, 129, 13410),
asymmetric epoxidation of ketones
(JACS 2008, 130, 10078), as well as
asymmetric oxetane formation from
racemic epoxides (ACIEE 2009, 48,
1677), using the Corey–Chaykovsky
reagent in conjunction with REMB
catalysts.
Image taken from Acc. Chem. Res. 2009, 42, 1117.
5
Masakatsu Shibasaki – 柴崎�正勝
Y. Ishihara
3) BINOL-based Lewis acid/Lewis base bifunctional catalysts
2) BINOL-based catalysts activated by phosphine oxide or arsine oxide
For a review by Shibasaki on this topic, see: J. Synth. Org. Chem. Jpn 2002, 60,
94–105.
Common achiral additives for REMB chemistry (see review in ACIEE 1999, 38,
1570–1577) include: Water, amines/pyridines (e.g., 2,6-lutidine); alcohols (e.g.,
tBuOH); ionic additives (e.g., LiCN, LiBF , NaOtBu, BuLi); phosphine and arsine
4
oxides.
i
O
Ph
La(O Pr)3 (10 mol%), (R)-BINOL (10 mol%)
tBuOOH (2 eq), additive, THF, rt
O
Ph without additive: 92%, 71% ee after 90 min
Ph
Ph3P=O (40 mol%): 98%, 97% ee after 30 min
Ph3As=O (10 mol%): 95%, 97% ee after 3 min
Baran Lab GM 2011-05-28
For reviews by Shibasaki on this topic, see: Synlett 2005, 1491–1508; Pure Appl.
Chem. 2005, 77, 2047–2052.
Proposed model:
Ligand (9 mol%)
Bu3P=O (36 mol%)
–40 ºC; then acid
O
R
37–96 h
R = alkyl, vinyl
most yields >95%;
most ee's >95%
Ph
H
O
Ph
Ligand:
JACS 2001,
123, 2725.
Lewis base
Experimentally, a 1:1:1 ratio of lanthanide:BINOL:Ph3As=O was best. However:
Lewis acid
Figures taken from JACS 2001,
123, 2725. The phenyl groups
on the arsenic atoms were
removed for clarity purposes.
HO
Ph
Lewis base
Al
O
Ph
H
P
O
Cl
R
CN
O
O
P
Image taken from JACS 1999, 121, 2641.
Ph
Scope: Only used for cyanosilylations of aldehydes and Reissert-type reactions.
Metal: Only Al.
R1
R1
O
O
N
N
Me
Me
CN
Due to the experimental observations
(1:1:1 being the best), a possible form
of the active catalyst in solution is as
follows:
Scope: Unlike the REMB catalysts,
this "rare earth metal"-BINOLarsenic combination is only good
for the asymmetric epoxidation of
unsaturated carbonyl groups. For
the asymmetric epoxidation of
enamides using Sm-BINOL-As,
see: JACS 2002, 124, 14544; for
unsaturated acylpyrroles, see:
JACS 2004, 126, 7559; for enoates
using Y-bisphenol-As, see: JACS
2005, 127, 8962.
Metal: La, Sm or Y.
N
R2
NC
N
JACS 2004, 126, 11808. CO2R
JACS 2001, 123, 10784.
1:2:3 ratio!
R2
CO2R
4) BINOL-based bimetallic catalysts
R
R
R
R
OLi
MCl3
O
OLi
M = Al, Ga
O
R
M
Li
O
O
R
Scope: Good for asymmetric epoxide openings, because they typically employ
stronger nucleophiles that displace the BINOL in REMB catalysts (JACS 1997, 119,
4783; ACIEE 1998, 37, 2223; JACS 2000, 122, 2252).
Metal: Good system for group 13 (Al, Ga) catalysts that do not coordinate very well in
multicoordinated REMB systems (ACIEE 1996, 35, 104; JACS 1998, 120, 441).
6
Masakatsu Shibasaki – 柴崎�正勝
Y. Ishihara
Baran Lab GM 2011-05-28
6) Salen-derived, "Schiff base bimetallic" catalysts
5) Linked BINOL-based catalysts
For reviews by Shibasaki on this topic, see: Adv. Synth. Catal. 2002, 344, 3–15;
Chem. Soc. Rev. 2006, 35, 269–279.
Shibasaki wanted a catalyst that is more stable to air and moisture, and an extra
ether linkage was all that was needed:
This is the latest series of binaphthyl-based ligands used in the Shibasaki lab,
first reported in 2007 and continues on to this day. For a partial review by
Shibasaki on this topic, see: Acc. Chem. Res. 2009, 42, 1117–1127.
*
Types of
N
N
OH
*
N
HO
OR
N
N
N
O
CO2Bn
RO
CO2Bn
CO2Bn
DME, rt, 72 h (M = H)
Week 0 of storage: 94%, >99% ee
Week 1 of storage: 93%, >99% ee
Week 2 of storage: 94%, >99% ee
Week 3 of storage: 94%, >99% ee
Week 4 of storage: 95%, >99% ee
X1 O
OR
+
M2X2n
N
N
M1
O
X1 O
M2
O
R
X2
O
R
If R = Me, M2 would have more X2s
around it to neutralize its formal charge.
Of note: The metal catalyst is
not necessarily monomeric, as
dimeric ones form easily with a
three-metal center.
Figure taken from JACS 2003, 125, 2169.
N
N
best one
N
N
This is a gold-mine catalyst!
*
Metal: Zn works best.
N
M2 = usually M(III); then X2 = halide, OAc, OTf, etc.
e.g., Mn, Co, Ga, Y, La, Pr, Nd, Sm, Eu, Gd, Dy, Er, Yb
But if M2 = M(II), then X2 = nothing
e.g., Ni, Cu, Zn, Pd
CO2Bn
Scope: Limited to aldol,
Mannich and Michael (soft
nucleophiles only) reactions.
N
M1 = usually M(II); then X1 = nothing
e.g., Mg, Ca, Ni, Cu, Zn, Sr, Rh, Pd, Ba
But if M1 = M(III), then X1 = halide, OAc, OTf, etc.
e.g., Al, Sc, Mn, Co, Ga, In, La, Nd, Sm, Gd, Er, Yb
N
M1
O
N
M1X1n
*
O
=
Ph
Me Me
RO
R = H or Me
Figures taken from:
JACS 2000, 122, 6506.
Ph
Representative publications in JACS:
2007, 129, 4900; 2008, 130, 2170;
2009, 131, 8384; 2009, 131, 9168;
2009, 131, 17082; 2010, 132, 1255;
2010, 132, 3666; 2010, 132, 4925;
2011, 133, 5791.
Representative publications in ACIEE:
2008, 47, 3230; 2009, 48, 2218; 2009,
48, 3353; 2011, 50, 4382.
Scope: Very broad. Nucleophile could be aldehydes/ketones, esters, amides,
vinyligous amides, nitroalkanes, alkyl isocyanides, isothiocyanates, oxindoles,
etc. Electrophile could be aldehydes/ketones, imines, unsaturated carbonyls and
unsaturated nitro compounds, and even Boc-N=N-Boc.
Metal: Pretty much any combination of M(II) or M(III) metals.
Downside: A lot of screening, even more so than for REMB catalysts.
7
Masakatsu Shibasaki – 柴崎�正勝
Y. Ishihara
9) Chiral Cu(I) catalysts
7) Tartrate-derived catalysts
Tartrate-derived ammonium salts (TaDiAS)
= Tartrate + Phase-transfer catalysis
TL 2002, 43, 9539; T 2004, 60,
7743; ACIEE 2005, 45, 4564.
Overall reaction:
CO2tBu
N
Ph
catalyst
N
Ph
Ph
Ph
If R bears a stereocenter,
high dr's can be achieved:
NBoc
+
R'
CO2tBu
N
Ph
*
CO2tBu
R
NHBoc
catalyst
(10 mol%)
Catalyst design:
R'
O
R'
O
N
Me
Me
N
CO2tBu
R'
Cs2CO3 (2 eq)
PhF or 4:1
PhF/pentane
Ph
N
Ph
Ph
Ar
Ar
2 X–
Ar
Ar
Reaction time: 19–72 h
Most yields >95%
All dr's >95:5
Most ee's 60–80% ee
Scope: The reaction itself could be anything: Michael, carbonyl addition, imine
addition, even SN2! This is essentially a good source for chiral α-amino acid.
Disadvantage: The system is highly sensitive to the nature of the solvent.
Sr(OiPr)2
CN Bu
Me
Me
racemic
ligand
PhMe
rt, 1 h
Scope: Limited to
cyanosilylation of
ketones, enones,
imines, and
aziridines.
Metal: Ti, Gd, Sr;
but try Gd first.
Of note: The metal
catalyst is not
necessarily
monomeric, as
tetrameric ones form
easily with a threemetal center.
O NC
Me
O
Ph2(O)P
HO
O
Me
Bu
100%, >99% ee
Ligand design:
R = H, F, Bz HO
Chiral bisphosphine
+
R
A kinetic and thermodynamic
conundrum: JACS 2009, 131,
3779.
diamide ligand (10 mol%)
Sc(OiPr)3 (5 mol%)
O
*
P
P
Cu
X
originally, X = F
but now it could
be anything...
S
OH
iPr
CN
R
NR2
diamide ligand (10 mol%)
Er(OiPr)3 (5 mol%)
EtOAc, 0 ºC, 4 h
95%, 99% ee, anti/syn = 6:94
Ligand design: R = iPr works best
R
H
N
HO
N
H
NHBoc
Ph
CN
+
Ph
O
O
EtOAc, 0 ºC, 12 h
98%, 91% ee, anti/syn = 91:9
NBoc
Sc gives anti and is slower
Er gives syn and is faster...
Figure taken
from JACS 2006,
128, 16438.
R1
*
OMe
(EtO)3SiF, DME
R2
then Et3N•HF JACS 2006, 128, 7164.
OMe
R2
R1
10) Amide-based catalysts
Newest class of ligands used in the Shibasaki laboratory, their first report in 2007
(JACS 2007, 129, 11342). But back to group III metals and lanthanides...
8) "CAPO" (catechol-phosphine oxide) ligands and "homopolymetallic" catalysts
A relatively new ligand from 2000 (JACS 2000,
122, 7412), uses of this ligand are still being
explored. The latest (JACS 2010, 132, 8862):
For reviews by Shibasaki on this topic, see: Pure Appl. Chem. 2008, 80, 1055–1062;
Chem. Rev. 2008, 108, 2853–2873.
Originally, achiral versions of desilylating reactions were studied, namely CuFaccelerated Sakurai (JACS 2002, 124, 6536) and Mukaiyama aldol reactions
(JACS 2003, 125, 5644). Fluoride anion was chosen by design (as a desilylating
agent), and copper cation was chosen by experimentation (Al, Zr, Hf chlorides
failed; AgCl was not bad; CuCl was best). CuF was generated in situ because it is
neither commercially available nor very stable.
OTMS
O
OH
CuF(PPh3)3•2 EtOH
Catalyst design:
O
Scope: The nucleophile is limited to alkenylsilanes,
allylsilanes, arylsilanes and silyl enol ethers. The electrophile
is limited to aldehydes, ketones, aldimines and ketimines.
Metal: Only Cu.
iPrCHO
These studies were not continued for
Cu(MeCN)4PF6
long (2005–2006). Now, Shibasaki
S
Bisphosphine
takes any nucleophile and mediates it
with Cu(I), without fluorides. A recent
report (JACS 2011, 133, 5554):
NR2 DMF, –60 ºC
Me
Removal of benzophenone is easily done with 0.2 M citric acid in THF; the
catalyst could be recovered easily from the reaction mixture.
HO
Baran Lab GM 2011-05-28
O
OH
O
NHBoc
Ph
CN
But if they add Sc AND Er, they get the anti
product in 89:11 dr, even though Sc is slower...
so they ran experiments wherein they add Er
first to a mixture of ligand, >2 eq of cyanoketone
and arylimine "1", followed by the addition of Sc
and another type of arylimine, arylimine "2". The
arylimine "1" underwent syn addition and
arylimine "2" underwent anti addition. So the Sc
reaction is slower but binds better to the ligand.
8
Masakatsu Shibasaki – 柴崎�正勝
Y. Ishihara
Synthesis of natural products (cont'd):
Synthesis of natural products using methodology developed in his laboratory:
Me
Me
Me
HH
O
(6 steps, 35%
overall; see p. 3
of this handout)
O
MeO
OTf
Me O
AcO
H
Me
Me
(–)-capnellene via
asymmetric Heck
O
[Pd(allyl)Cl]2 (2.5 mol%)
(S)-BINAP (6.3 mol%)
NaBr, DMSO, rt, then
TBDPSO-CH2CH2-C(CO2Et)2Na
JACS 1996, 118, 7108.
OH
HH
Me
OBz
E
1) Bu3SnH,
AIBN
2) NaOH,
MeOH
(96% over
2 steps)
H
1) Et2Zn, CH2I2
(95%)
2) H2 (1 atm),
PtOH, rt (80%)
HH
N
Me
Me
HH
H
16
O
H
20
15
O
H
16
O
(–)-strychnine via
asymmetric Michael
11 steps
JACS 2002,
124, 14546; T
2004, 60, 7743.
O
(±)-wortmannin via
diastereoselective Heck
N
H
N
H
SEM-O
Zn, MeOH
aq. NH4Cl
PMB-O
iPr
4
O
S
EtCN, –40 ºC, 2 days
>99%, 98% ee
(6 steps from
6 gram scale
isovaleraldehyde) recoverable ligand
HO
2
CO2H
(+)-lactacystin via
asymmetric Strecker
O
16
15
H
20
H 15
O2N
O
SEM-O
16
H
HO
"FujiCAPO" ligand:
O
HO
CO2H
NHAc
Et3N, CH2Cl2 (58%)
O
7 8
6
5
F
NH
F
4
EtO2C
Protic additives "dramatically improve "the
enantioselectivity, the catalyst turnover
number, and the turnover frequency."
Me
O
JOC 2006, 71, 1220.
iPr
O
iPrMgBr
(3.5 eq)
75%,10:1 dr
O
Me
NH
20
O
OH
Et3N,
CH2Cl2
(>63%)
NH
NH
BOP-Cl
iPr
O
PMB-O
O
SH
CO2Me
NH
6 steps
involving
ozonolysis
9
CO2Me
18 steps
(EtS)2HC
6
7
8
O
Ph2(O)P
NHAc
> 77%
H
Gd(HMDS)3 (2.5 mol%)
4
NP(O)Ph2 Ligand (3.8 mol%)
NC NHP(O)Ph2
TMSCN (2 eq)
2,6-Me2phenol (1 eq) iPr 9 5
iPr
NH
9
2) H2O2, K2CO3, rt
(78% over 2 steps)
MS 4Å, THF
91%, >99% ee
kilogram-scale
no chromatography
Et
Formal synthesis (3 steps away from natural
product): JACS 2001, 123, 9908; TL 2002,
43, 2923; Heterocycles 2003, 59, 369.
See Ke Chen GM 2007
O
HO
(–)-capnellene
HO
(20S)-camptothecin via
asymmetric cyanosilylation
Me
ALB = Al-Li-bis(binaphthoxide)
(EtS)2HC
O
N
O
7 8
6
5
1) 2-nitrophenylSeCN
PBu3, pyridine, rt
N
H
OTBS
Me
(77%, 87% ee)
Dimethyl malonate
(R)-ALB (0.1 mol%)
KOtBu (0.09 mol%)
H 15
O
OH
Me
N
(78% over
6 steps)
I
O
H
Total synthesis:
ACIEE 2002, 41, 4680;
T 2005, 61, 5057.
See Gutekunst GM 2011
E
HH
Me
O
Me
O
Me
Baran Lab GM 2011-05-28
iPr
HO
O
HO
OH
iPr
9 steps involving a
Si 1,4-addition and O
Tamao–Fleming [O]
HO
OEt
9
Masakatsu Shibasaki – 柴崎�正勝
Y. Ishihara
Synthesis of natural products (cont'd):
S
Et2AlCl (5 mol%)
BINOL derivative (5 mol%)
Bu3P=O (20 mol%)
TMSCN (1.2 eq)
CH2Cl2, –40 ºC, 48 h
S
Me
Me
N
N
H
Me
O
then TFA
(97%,
99% ee)
O
O
Me
OH
O
Me
Me
R
HO
O
O
10
Me
OH
OH
8
5
Me
H
OAc
8 steps
R
I
CN
Me
Ti(OiPr)4 (5 mol%)
FujiCAPO ligand
TMSCN, –25 ºC
93%, 85% ee
OH
OL 2003, 5, 733;
JACS 2005, 127,
17111.
O
O
Me
13
O
O
SiMe3
"vinyl iodide"
Me
BnO
OMOM
8
5
Me
Allyl-Si(OMe)3
BINAP deriv.
AgF (20 mol%)
80%, 28:1 dr
11
10
O
8
5
13
11
(S)-LLB
65%, 3.6:1 dr
OH
Me
BnO
(+)-fostriecin via enantioselective cyanosilylation,
then diastereoselective allylation and aldol
N
H
(–)-epothilone A (R=H) and (–)epothilone B (R=Me) via
asymmetric cyanosilylation and
Michael reactions
O
many steps
N
Me
ONa
P
O
Me
Me
O
OH
Synthesis of natural products (cont'd):
S
S
Me
Baran Lab GM 2011-05-28
then 4 steps
CN
9
OTMS
6 steps
OTIPS
O
Me
OMOM
ACIEE 2000, 39, 209; JACS 2000, 122, 10521.
SEt
4-tBuC6H4SH
SmSB (5 mol%)
tBuC
O
O
92%, 88% ee
Me
Ph
O
7 steps
Me
O
Me KHMDS,
Me PhCOMe
Me
O
Me
Me
(1:1 dr)
O
Me
Me
1) TMSOOTMS, SnCl4,
sulfonamide ligand
2) BCl3
3) TBSOTf
4) DMP
O
O
Me
PhO
BnO
Me
Me
4 steps
Me
Me
OH
HO
O
(39% over
4 steps)
Me
O
NH
H
N
O
N
H
followed by 6 final steps
JACS 2003,
125, 11206;
PNAS 2004,
101, 5433.
O
La-(S)-BINOL
t
imid BuOOH, MS 4Å
TIPSO
Ph
epothilones
NH2
OH
Ph
(becomes left
portion of molecule)
TIPSO
N
RO
RO
TaDiAS catalyst
+
CO2tBu
O
OOtBu
RO
RO
Me 9-BBN; then "vinyl iodide",
K3PO4, PdCl2(dppf), 60 ºC
Me
O
OTBS
N
95%, 94% ee
OTBS
Me
N
H
O
OH
Me
H
H
(??)-aeruginosin 298-A via asymmetric alkylations and epoxidation
Me
O
*??: reported as (–) in
Bonjoch et al., Chem.
Eur. J. 2001, 7, 3446.
iPr
Me
Me
Me
O
EtCOCMe2CH2OBn
+ LDA (4:1 dr)
O
OH
HO
*??: reported as
(+) in Wipf et al.,
OL 2000, 2, 4213.
SEt
6H4-S
80%, 88% ee
Br
N
Ph
Ph
(becomes
middle
portion of
molecule)
CO2tBu
10
Masakatsu Shibasaki – 柴崎�正勝
Y. Ishihara
Synthesis of bioactive molecules:
Synthesis of natural products (cont'd):
Me
Me
Me
Me
O
HO
O
O
O
3
4
Me
O
O
O
O
Me
5
Me
FeBr3 (10 mol%)
AgSbF6 (20 mol%)
Ligand (12 mol%)
5Å MS, CH2Cl2
–70 ºC, 30 h
(93%, 96% ee)
OTIPS
8
Me
Me
1
O
O
5
6
O
O
N
Ar
O
Ar- = 4-EtOC6H4(5-step synthesis)
Me
5
Me
Me
Me
O
iPr
7
Me
Me
Me
Me
20 steps involving
an enolate SN2 for
the C5 prenylation
and a Claisen
rearrangement of
an allyl enol ether
to place C2–C4
15 more steps
O
3
5
8 steps including an
aldol to form the C4–
C5 bond, and a crossMe metathesis to install MOMO
the C7 prenyl group
from an allyl group
•H3PO4
+
7
Me
OH
CO2Me
91%, 5:1 dr
95% ee
58 g scale
CO2Me
1) NaOH
2) DPPA
3) tBuOH, ∆
4) Ac2O
(93% overall)
(2.5 mol% in each of
the 3 components;
see right side of p.9
for ligand structure)
NHAc
AcO
OH
iPr
NHAc
Me
EtO2C
O
AcO
1) TFAA, urea•H2O2,
Na2HPO4, 4 ºC
2) K2CO3, EtOH, rt
NC
Me
Ba(OiPr)2
F2-FujiCAPO
CsF, –20ºC
then aq. HCl
"4th generation": ACIEE 2009, 48, 1070.
O
1
(+)-cylindricine C
C6H4-4-Me
MeO2C
NH2
EtO2C
2
O
4
O
Tamiflu® via
asymmetric Diels–Alder
Ar
O
N
1) CSA, LiCl
2) H2, Pd/C
3) ClCO2Et;
then NaBH4
C6H4-4-Me
2 BF4–
C6H4-4-Me
CO2Me
NHAc
O
N
Me
Me
C6H13
Ph
C6H4-4-Me
OTMS
Me
O
(–)-ent-hyperforin
O
Me
OTIPS
O
N
N
Bn
8
7
N
(8-step synthesis)
4
O
Me
Me
Me
"(S,S)-TaDiAS" ligand:
O
BnO2C
Ph
Bn
Me
10
84%, 82% ee
O
O
N
C6H13
Ph
ACIEE 2006, 45, 4635.
OTIPS
Ligand:
N
BnO2C
Ph
C6H13
OL 2004, 6, 4387; ACIEE 2010, 49, 1103.
OTIPS
10
N
(+)-cylindricine C via
asymmetric Michael
(+)-hyperforin
(first synthesis of its enantiomer,
via asymmetric Diels–Alder)
JACS 2005, 127, 14200.
1
HO
Me
Me
(±)-garsubellin A
(first synthesis, 23 steps,
0.43% overall)
Ligand (10 mol%)
Cs2CO3 (1 eq)
3-fluorotoluene
–40 ºC, 66 h
O
N
10 iPr
1
8
Me
Me
2
O
5
Me
Me
Me
7
Me
HO
Me
iPr
Me
6
Baran Lab GM 2011-05-28
NHBoc
CN
1) PPh3, DEAD,
p-O2N-C6H4CO2H;
then LiOH, EtOH
2) Me2PPh, DIAD
NHBoc
(49% for 4 steps)
EtO2C
H
O
NAc
NC
CN
[Pd]
(85%)
NHBoc
(recrystallize to
>99% ee here)
1) BF3•OEt2,
NAc 3-pentanol
2) TFA; H3PO4
(55%)
NHBoc
Tamiflu®
Tamiflu®
For other syntheses of
by Shibasaki, see: 1st: JACS 2006, 128,
6312; 2nd: OL 2007, 9, 259; 3rd: TL 2007, 48, 1403.
11